Identification of Long stress-induced non-coding transcripts that have altered expression in cancer

Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Genomics (Impact Factor: 2.28). 03/2010; 95(6):355-62. DOI: 10.1016/j.ygeno.2010.02.009
Source: PubMed


It has recently become clear that the transcriptional output of the human genome is far more abundant than previously anticipated, with the vast majority of transcripts not coding for protein. Utilizing whole-genome tiling arrays, we analyzed the transcription across the entire genome in both normal human bronchial epithelial cells (NHBE) and NHBE cells exposed to the tobacco carcinogen NNK. Our efforts focused on the characterization of non-coding transcripts that were greater than 300 nucleotides in length and whose expression was increased in response to NNK. We identified 12 Long Stress-Induced Non-coding Transcripts that we term LSINCTs. Northern blot analysis revealed that these transcripts were larger than predicted from the tiling array data. Quantitative real-time RT-PCR performed across a panel of normal cell lines indicates that these transcripts are more abundantly expressed in rapidly growing tissues or in tissues that are more prone to cellular stress. These transcripts that have increased expression after exposure to NNK also had increased expression in a number of lung cancer cell lines and also in many breast cancer cell lines. Collectively, our results identified a new class of long stress responsive non-coding transcripts, LSINCTs, which have increased expression in response to DNA damage induced by NNK. LSINCTs interestingly also have increased expression in a number of cancer-derived cell lines, indicating that the expression is increased in both, correlating cellular stress and cancer.

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Available from: David I Smith, Mar 06, 2015
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    • "Upon exposure to environmental stressors such as ultraviolet-B irradiation, viral infection and translational inhibitors, specific lncRNAs are expressed (Sonkoly, et al.,2005). More specifically, a group of large intergenic ncRNAs (lincRNAs) were found to be involved in response to DNA damage which was regulated by the p53 pathway (Silva, et al.,2010; Mizutani, et al.,2012; Zhang, et al.,2013). "
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    ABSTRACT: In the present study, the role of lncRNAs in response to radiation-induced DNA damage and oxidative stress were explored to improve our understanding of the biological pathways activated upon radiation-induced toxicity. The toxicity of X-ray radiation on human bronchial epithelial cell lines (HBE) was determined through a dose-dependent increase in ROS production and γ-H2AX formation and changes to lncRNA expression was observed quantified using lncRNA-specific microarrays. We 115 lncRNAs whose expression was increased in a dose-dependent manner following X-ray irradiation.. After Biolnformatic prediction algorithms determined that these lncRNAs significantly affect the p53 signaling pathway, and, more specifically, the BRCA1 transcription factor.and coding genes adjacent to BRCA1. Our results highlight a previously uncharacterized role for lncRNAs acting via the p53-pathway in response to X-ray-induced DNA damage, and suggests lncRNAs may serve as novel indicators for radiation toxicity.
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    • "For example, Silva et al., 2010 analyzed transcription across the entire genome in both normal human bronchial epithelial cells (NHBE) and NHBE cells exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK). Twelve long stress-induced noncoding transcripts (LSINCTs) were identified (Silva et al., 2010). We then examined, for the first time, the lncRNA expression profiles in 16HBE-T cells and found that a small number of lncRNAs were abnormally expressed, with changes greater than 2.0-fold. "
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    ABSTRACT: Lung cancer is the leading cause of cancer deaths and remains an important public health problem worldwide. Long noncoding RNAs (lncRNAs) are newly identified regulators of tumorigenesis and tumor progression. However, the role of lncRNAs in lung cancer induced by environmental carcinogens remains largely unknown. In this study, an lncRNA microarray was used to compare the expression profiles of malignantly transformed 16HBE cells (16HBE-T) induced with anti-benzo[a]pyrene-trans-7,8-diol-9,10-epoxide (anti-BPDE) and normal 16HBE cells (16HBE-N). Using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), lncRNA AF118081 was identified as the most significantly overexpressed lncRNA in 16HBE-T cells, lung cancer cells, and patient samples. Cell proliferation, colony formation, apoptosis, migration, and invasion were assayed in 16HBE-T cells following the knockdown of lncRNA AF118081 with small interfering RNA. AF118081 knockdown inhibited cell growth and tumor invasion. An in vivo (nude mouse) model was then used to assay tumor growth, and the downregulation of AF118081 clearly suppressed tumor growth, consistent with the results of the in vitro assays. Together, these findings identify a new oncogenic lncRNA, lncRNA AF118081, in malignantly transformed 16HBE cells. This enhances our understanding of lncRNAs as important regulatory elements in chemical carcinogenesis and potential targets of lung cancer therapies.
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    • "lncRNAs are dysregulated in a number of human diseases, including several cancers and neurological disorders and show tissue-specific expression [36]. Several lncRNA have increased expression in a number of cancer cells [37]. Genotoxic stress-inducible nuclear lncRNA have been identified [38]. "
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